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PCSK9 Inhibitors: A New Class of Cholesterol Busters

Medically reviewed on Jan 12, 2017 by L. Anderson, PharmD

Flashback: A Review of Statins

By now you've heard of statins, also known as HMG-CoA reductase inhibitors. Statins are the cornerstone of treatment to help regulate cholesterol production. Available since the late 1980's, statins include well-known blockbusters like atorvastatin (Lipitor), simvastatin (Zocor), and rosuvastatin (Crestor). Statins work so well because they inhibit an enzyme involved in the making of cholesterol in the liver and boost the number of low density lipoprotein receptors (LDL-R) to help clear the body of LDL ("bad cholesterol). However, as researchers have reported in Annals of Internal Medicine, a new class of drugs may change the face of lowering LDL cholesterol.

What Are PCSK9 Inhibitors?

The PCSK9 inhibitors (PSK9i) are a newer class of injectable drugs that have been shown to dramatically lower LDL cholesterol levels, by up to 60% when combined with a statin. PCSK9 inhibitors are monoclonal antibodies (MABs), a type of biologic drug. They bind to and inactivate a protein in the liver called proprotein convertase subtilisin kexin 9 (PCSK9). PCSK9 itself inactivates the needed receptors on the liver cell surface that transport LDL into the liver for metabolism (break down). Without these receptors, more LDL ("bad" cholesterol) remains in the blood. So, by inactivating PCSK9 via inhibition, more receptors are available to capture LDL for metabolism and removal from the blood. And, as we know, lower LDL is better for the heart.

Who Needs a PCSK9 Inhibitor?

There are roughly 37 million adults in the U.S. whose high cholesterol is not treated, with about 11 million who cannot reach their LDL cholesterol goals, even though they have been on a first-line treatment like statins. In fact, about 1 in 5 patients on statins cannot lower their cholesterol adequately at all; some due to serious genetic defects. In addition, some patients stop their statin treatment due to side effects. PCSK9 inhibitors may be used alone or in combination with statins to further lower the hardest-to-treat elevated cholesterol levels for patients who cannot tolerate any statin drug.

Clinical Studies for PCSK9 Inhibitors

Several PCSK9 studies were published in the New England Journal of Medicine (NEJM) in March 2015. The studies show that two agents, evolocumab (Repatha) or alirocumab (Praluent), when combined with statins, lower cholesterol better than the statin alone. After one year, those patients who were taking both the PCSK9 inhibitor and the statin together had LDL levels that were at least 60 percent lower than the group taking only statins. LDL levels dropped dramatically. Larger studies are ongoing to evaluate PCSK9 inhibitors on the ability to lower outcomes like heart attack or stroke, but early results suggest cardiovascular events could be lowered by half.

PCSK9 Inhibitors: Just the Basic Facts

Here is a sampling of what we know so far with this new class of drugs. PCSK9 inhibitors are given by subcutaneous (under the skin) injection, via self-administration with a pen device, one or two times per month. In general, PCSK9 inhibitors have been well-tolerated, but the common cold, itching, flu, injection site reactions, and serious allergic reactions have been reported. Injection site reactions are the most common reaction but infrequently lead to discontinuation of treatment.

More studies of a larger population size are ongoing to fully define outcomes like prevention of heart attack, stroke, and other cardiovascular disease. These drugs are monoclonal antibodies (MABs), an expensive drug type, and cost roughly $14,000 per year in the US. They are also approved in the European Union.

Praluent (alirocumab) by Sanofi/Regeneron

In July 2015, alirocumab (Praluent) by Sanofi and Regeneron was the first PCSK9 inhibitor to receive an FDA-approval.

Clinical studies included ODYSSEY, an 18-month, phase 3 trial of 2,341 high-risk patients with high cholesterol on statin therapy. LDL was reduced over 60 percent after 24 weeks, and remained low over 78 weeks. Ongoing trials with Praluent are assessing cardiovascular outcomes like heart attack or stroke.

Praluent Side Effects

Praluent was evaluated in five placebo-controlled trials involving 2,476 patients. All patients had HeFH or were otherwise at high risk for heart attack or stroke, and were taking maximally tolerated doses of a statin. Participants taking Praluent had an LDL reduction from 36 to 59 percent compared to placebo. The most common side effects have included nasopharyngitis (common cold), injection site reactions, and influenza. Serious allergic reactions were also reported. There are no known drug interactions with Praluent.

The incidence of pre-specified cardiac adverse events like heart attack or stroke were lower in the alirocumab group (1.7%) compared to placebo (3.3%), but full cardiovascular outcomes are not known yet.

Repatha (evolocumab) by Amgen

Repatha (evolocumab) was FDA-approved in August of 2015. Repatha injection is indicated for use in addition to diet and maximally-tolerated statin therapy in adult patients with heterozygous familial hypercholesterolemia (HeFH), homozygous familial hypercholesterolemia (HoFH), or clinical atherosclerotic cardiovascular disease (ASCVD), such as a heart attack or stroke, who require additional lowering of LDL cholesterol. In Phase 3 clinical trials, Repatha lowered LDL by roughly 60% across all study groups in 12 week and 52-week studies; Repatha reduced LDL cholesterol levels by 61% (from a median of 120 mg/dL to 48 mg/dL over 12 weeks. In HoFH, Repatha reduced LDL by 31%.

Side Effects with Repatha

In the OSLER-1 and OSLER-2 open-label studies, side effects that occurred with Repatha at a rate of at least 1% included arthralgia (joint pain, 4.6%), injection site reactions (4.3%), headache (3.6%), limb pain (3.3%), and fatigue (2.8%). Injection site reactions rarely lead to discontinuation of PCSK9 inhibitors.

Neurocognitive effects like confusion were low (under 1%). Evolocumab was stopped in 7.2% of 2976 patients. Very low levels of LDL did not appear to affect rates of side effects. Other side effects include the common cold, upper respiratory tract infections, and injection site reactions. No clinically important drug interactions have been identified with Repatha.

PCSK9 Dosing

The recommended dose of Repatha (evolocumab):

  • 140 mg subcutaneously (abdomen, thigh, or upper arm) every two weeks or 420 mg once monthly for primary hyperlipidemia with established clinical atherosclerotic CVD or heterozygous familial hypercholesterolemia (HeFH).
  • For homozygous familial hypercholesterolemia (HoFH), the approved dose is 420 mg subcutaneously once monthly or 420 mg every two weeks.
The initial dose of Praluent (alirocumab):
  • 75 mg subcutaneously once every two weeks; most patients will achieve adequate LDL lowering with this dose.
  • LDL plasma levels should be measured within 4 to 8 weeks of initiating or changing the dose and an increase in dosage to 150 mg can be initiated if LDL lowering is inadequate.
If a dose is missed, administer the injection within 7 days from the missed dose and then resume your original schedule. If the missed dose is not given within 7 days, you should wait until the next dose on the original schedule.

Ongoing PCSKi Questions

Analysts predict that Repatha and Praluent could each generate annual sales of over $1 billion by 2020. Managed care experts suggest this new class of drug could add considerable costs to statin therapy - which primarily exist in generic - and very affordable form - now. However, treatment targets the highest-risk patients who cannot reach adequate LDL levels with statins.

Some studies are looking at monotherapy with PCSK9 inhibitors, too. While the levels of cholesterol lowering are dramatic, experts are quick to point out that ongoing research will determine if ill-effects occur from such large LDL reductions.

Bococizumab Studies Halted

In November 2016, Pfizer discontinued the global development of bococizumab, their investigational PCSK inhibitor, as well as the two ongoing cardiovascular outcome studies, SPIRE-1 and SPIRE-2.

Pfizer stated that unexpected results occurred in looking at the outcomes of six Phase III studies. Compared to current agents in this class, LDL lowering over time with bococizumab was not as robust, and a higher level of immunogenicity and a higher rate of injection-site reactions also occurred. Due to lack of value to shareholders, especially in the currently marketplace, Pfizer decided to halt the studies worldwide.

Alternate Mechanisms: PCSK9

In addition to blocking the PCSK9 receptor to lower LDL, blocking the synthesis of PCSK9 can lower LDL levels. Synthesis of PCSK9 requires mRNA. Phase I dose-ranging studies have looked at degradation of the mRNA needed for PCSK9 development with a compound called ALN-PCS (inclisiran) from Alnylam Pharmaceuticals/The Medicines Company.

In a Phase I study published in the New England Journal of Medicine in early 2017, inclisiran (ALN-PCS) doses of 300 mg or more (in single or multiple doses) significantly reduced levels of PCSK9 (~75%) and LDL cholesterol (~50%) for at least 6 months. The most common adverse events were cough, musculoskeletal pain, cold/runny nose, headache, back pain, and diarrhea. Further studies to investigate effectiveness, safety and long-term use, and FDA-approval, will need to be completed before clinical use.

Lifestyle is Still an Important Adjunct

Everyone should partake in a healthy lifestyle, whether they have high cholesterol or not. We know you've heard this before, but it really is important:

  • Quit smoking
  • Eat a low fat, low salt diet
  • Exercise 30 to 40 minutes a day on most days of the week
  • Control your stress, learn to relax
If your cholesterol and LDL levels remains high, even with lifestyle changes, medications to improve your cholesterol might be needed to help prevent heart disease and stroke. The statins, PCSK9 inhibitors, and upcoming investigational agents may offer hope to millions trying to achieve their cardiovascular goals.

Finished: PCSK9 Inhibitors: A New Class of Cholesterol Busters

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